Abstract The current proposal employs a vaccine platform, originally developed for malaria, to elicit protective immunity to Zika virus infection. The novel vaccine platform employs fusion of the vaccine antigen to a series of virus-derived chemokine-like molecules to direct the vaccine antigen to the immature dendritic cells that initiate the adaptive immune response. This vaccine construct will be used in combination with the MF59 adjuvant, which has been approved for clinical use in pregnant women for other vaccines by the US FDA. In its initial iteration including the human-derived chemokine MIP3? (CCL20), this vaccine platform has proven to be remarkably effective at eliciting high concentrations of antibody and protective immunity in a malaria mouse model challenge system. To avoid use of human-derived products in the vaccine construct MIP3? will be replaced in the currently proposed studies with the viral chemokines, for which similar immune enhancing capabilities have been observed. Domain III of the Zika virus E protein, which lacks N-linked glycosylation sites, will be targeted because of the ease of its expression in bacterial expression systems. Initial studies will optimize the vaccine construct, ensuring proper conformation and evaluating the affinity and magnitude of antibody responses elicited in wild-type C57BL/6 mice receiving different vaccine dosing regimens. Subsequent studies will evaluate the maintenance of protective antibody concentrations over a six month period, using both in vitro PRNT assays and in vivo challenge systems. For longevity of protection studies, in vivo challenge will be performed evaluating the protective efficacy of passively transferred antibody in Irf-3, 5 and 7 triple knockout mice available at this institution, These mice, under 11 weeks of age, have been demonstrated to be susceptible to Zika virus infection.